McClure's XMRV Contamination Conversation

Professor Myra McClure has been popping up quite a lot in the media recently, casting doubt on the positive MuLV/XMRV studies. The very incisive mind of cfssufferer has turned a spotlight on a series of emails with McClure, examining her theories of contamination.

Professor McClure has publically stated on many occasions that there is a high possibility that the XMRV/MLV related virus findings being implicated in CFS are a consequence of contamination.

The conclusion reads
"Professor McClure has used numerous fallacies, logical inconsistencies, explicit contradictions and flawed arguments to support her conclusion that contamination is the most likely explanation for the CFS-XMRV/MLV results. I have demonstrated that some of these arguments that Professor McClure has presented to support the contamination conclusion, inadvertently provide more weight against the contamination hypothesis. Contrary to Professor McClures claims, I have demonstrated that the weight of evidence strongly supports the XMRV/MLV- CFS link arising due to a pure retroviral-illness correlation as opposed to contamination."

It's a shame Prof. McClure did not say why those facts mentioned by the blogger (microscope picture, antibodies, ability to infect human cells etc.) don't rule out contamination. That would have been interesting.

But i agree, the issue will be settled.

One thing that i think she's right about, why didn't the WPI and Lo et al. blind the samples? I don't think this is a very big effort and it understandably seems to make a very big difference for the credibility of a result.

I think i'll abstain from reading much more coming from this camp and just wait for more studies.

That's she's becoming such a vocal denier, might be a last ditch effort to protect her career. If an XMRV connection is proven, her research is open for attack again. It certainly would not look good on her resume as a professor and researcher.
It could also be she's really convinced the virus does not exist or that contamination is an issue here.

One thing I have learnt is that these professors and researchers are humans like us (scary thought, huh?). They have their own agendas and careers and they are not always acting in our best interest.

McClure would have to genuinely believe it's contamination. As people are saying, it will come out in the end one way or the other and no-ones going to be able to spin it or cover it up, especially now we have the Alter paper. She could well be rather emotionally involved given the response to her paper and the animosity between her and Mikovits, but it would be crazy for her to be so anti-XMRV/CFS is she really thought the evidence supported a link.

I'm still suspicious of XMRV and CFS myself. I wish we had more clarity on the blinding done for the two positive studies (something McClure mentions) and more information about how the WPI was able to select CFS patients that were reported as being 95% positive - that sounds wierdly homogenous for a disease like CFS. At the same time - two positive studies from four labs with more expected - it would be strange if this wasn't something significant.

The Lombardi study was blinded (although Alter/Lo was not). Lombardi and Mikovits made clear the fact that their study was blinded in their response to comments in Science magazine. It's extremely difficult to believe that McClure had not read that published response, so I would classify her response to cfssufferer as deliberate misinformation. Cfssufferer has already edited his blog to correct this information, btw; it now reads:

Professor McClure has stated that the Science and PNAS papers had “CFS samples and control samples (that) have not been blinded, randomised and treated in exactly the same way at the same time.” This argument is used by Professor McClure as a potential mechanism to explain how the CFS samples were contaminated while the control samples were largely unaffected. Professor McClure has falsely associated these non-procedures with the Lombardi et al. paper as explained by Mikovits et al. in a ‘technical comments’ addendum to the Science paper. Mikovits et al. state that “All samples were blinded, as mandated by the NCI and WPI institutional review board approvals. All experimental procedures were done by the same personnel, in the same physical laboratory space, under identical protocols. Investigators at NCI received 100 samples from individuals without knowing their health status; furthermore, the samples were sent to NCI directly without passing through the WPI laboratory space. Laboratory workers at the NCI and the WPI who performed the polymerase chain reaction (PCR) and immunological studies used coded, blinded samples that did not reveal the CFS status of the individuals.” These technical comments can be found here http://www.sciencemag.org/cgi/content/full/328/5980/825-d

Professor McClure has erroneous information concerning this crucial aspect of the Lombardi et al. study. Contrary to Professor McClure’s assertion, the CFS samples and control samples in the Lombardi et al. study were in fact “blinded, randomised and treated in exactly the same way at the same time.” McClure’s contamination argument seems largely contingent on her erroneous piece of information. With this new information, Professor McClure’s conclusion that the “weight of evidence indicates laboratory contamination” is further jeopardised. If Professor McClure is to maintain her contamination hypothesis, she must now provide a mechanism explaining how contamination occurred in only the CFS sample subset that was part of the larger set of blinded and coded samples that were treated in an identical manner.

Professor McClure is correct in that the Lo et al. study was not blinded or randomized. Dr. Alter has explained that “We did not specifically blind and mix the two sample groups (CFS and blood donors.) However, they were studied in parallel by polymerase chain reaction (PCR).” Dr. Alter’s assertion that the samples were “studied in parallel” is reiterated by the Lo et al. paper itself which states “PBMC DNA (30–40 ng) from the CFS patients and the healthy blood donors, as well as serial dilutions from 50 to 1 fg of mouse DNA mixed with 35 ng of human DNA as the positive templates, were tested in parallel.”Another section of the Lo et al paper says, “All patient and control samples were coded and tested in parallel.” If both the CFS group and control group samples were tested as part of a continuum in a random sample order then the contamination likelihood is very small.

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Anyway, this is another outstanding article by cfssufferer, and I highly recommend reading it to anyone who has not. I made the following comments about McClure's email on mecfsforums.com, but am re-posting them here...

One of McClure's quotes that he hammers away at deserves even more hammering:

I would think that the onus is now on the Whittemore Institute to prove beyond all doubt that they are right when the rest of the world cannot reproduce their findings

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McClure is not speaking like a scientist here. First, she herself has maintained that the WPI cannot 'prove' anything because their lab and/or samples are contaminated, so how logically can they ever prove anything to her? Second she leaves out the NCI and the Cleveland Clinic, as she always does, who also tested samples for the Science study. If she maintains that they received contaminated samples, then she has the Alter/Lo paper to contend with - yet she also maintains that they had a separate form of mouse contamination. Now two questions arise - how did both labs get MLV contamination, and why would you assume that it's contamination until proven otherwise? Logic, probability and evidence all argue against contamination; the only argument to the contrary that she raises is the inability of her and a number of other labs to find the virus. The fact that the the two or three labs involved in the CDC study could not find it is at best no more relevant than the NCI and Cleveland Clinic finding it; all samples in the CDC study came from the CDC. If the sample collection, cohort selection or methodologies were inadequate, then the number of labs involved does not improve the chances of success. Similarly, as cfssufferer pointed out, the number of negative studies is not important; it's the fidelity of replication in science that matters, and McClure knows that (one hopes). Until someone does a true replication study, no scientist worth her salt would say that the burden of proof lies on the WPI. Nobody has published such a study yet, certainly not McClure. The only researcher undertaking such a study who has reported results, Maureen Hanson, has had positive results, a fact McClure omitted. Her argument about absence of evidence (as she perceives it) supporting the contamination idea is very similar to the psych lobby's contention that unless a disease can be proven to be physical, it is psychosomatic.

She also leaves out the fact that the CDC has tested positive samples from both the WPI and from the FDA and found them all negative. If those samples were positive due to contamination, why did the CDC's assays not pick up the alleged contaminants?

And how she can argue that the mutation of viral sequences in samples from the same patients taken 15 years apart can be explained by contamination is beyond me.

The Lombardi study was blinded (although Alter/Lo was not). Lombardi and Mikovits made clear the fact that their study was blinded in their response to comments in Science magazine. It's extremely difficult to believe that McClure had not read that published response, so I would classify her response to cfssufferer as deliberate misinformation. Cfssufferer has already edited his blog to correct this information, btw; it now reads:

Anyway, this is another outstanding article by cfssufferer, and I highly recommend reading it to anyone who has not. I made the following comments about McClure's email on mecfsforums.com, but am re-posting them here...

One of McClure's quotes that he hammers away at deserves even more hammering:

McClure is not speaking like a scientist here. First, she herself has maintained that the WPI cannot 'prove' anything because their lab and/or samples are contaminated, so how logically can they ever prove anything to her? Second she leaves out the NCI and the Cleveland Clinic, as she always does, who also tested samples for the Science study. If she maintains that they received contaminated samples, then she has the Alter/Lo paper to contend with - yet she also maintains that they had a separate form of mouse contamination. Now two questions arise - how did both labs get MLV contamination, and why would you assume that it's contamination until proven otherwise? Logic, probability and evidence all argue against contamination; the only argument to the contrary that she raises is the inability of her and a number of other labs to find the virus. The fact that the the two or three labs involved in the CDC study could not find it is at best no more relevant than the NCI and Cleveland Clinic finding it; all samples in the CDC study came from the CDC. If the sample collection, cohort selection or methodologies were inadequate, then the number of labs involved does not improve the chances of success. Similarly, as cfssufferer pointed out, the number of negative studies is not important; it's the fidelity of replication in science that matters, and McClure knows that (one hopes). Until someone does a true replication study, no scientist worth her salt would say that the burden of proof lies on the WPI. Nobody has published such a study yet, certainly not McClure. The only researcher undertaking such a study who has reported results, Maureen Hanson, has had positive results, a fact McClure omitted. Her argument about absence of evidence (as she perceives it) supporting the contamination idea is very similar to the psych lobby's contention that unless a disease can be proven to be physical, it is psychosomatic.

She also leaves out the fact that the CDC has tested positive samples from both the WPI and from the FDA and found them all negative. If those samples were positive due to contamination, why did the CDC's assays not pick up the alleged contaminants?

And how she can argue that the mutation of viral sequences in samples from the same patients taken 15 years apart can be explained by contamination is beyond me.

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Well done! We should send this to her -except that she knows all of it and is just not interested. I think she will rue her very public words over time. She is really out in front on this issue.

If i was an author of the Lombardi et al. science study i would consider to take legal steps against those saying the study was not blinded then (oops, now that even includes me, i think).
This is clearly a statement that hurts ones reputation as a scientist and oviously it's wrong.

Unfortunately that seems to be a bit harder. Maybe that's also a good thing because you don't want to restrict free speech, science, etc. too much.

If you say something that is not true, even if you're not aware that it's not true (the only thing that matters is wheter you can prove the truth of your statement or not), then, if that statement has the potential to hurt one's reputation, you've commited an offense and can be punished (if some other requirements are met, like you're not mentally ill etc.).

And you might have to publicly correct your statement and perhaps pay damages, depending on the case and legal system.

So i think Dr. Mikovits and her co-authors could do something against the people telling these things, if they want to, for XMRV positive people, probably that approach would not be successful.

If your doctor tells you XMRV does not mean anything, and that leads to a deterioration of your health or additional costs for you, you might be able to do something, but only because your doctor has a special sort of relationship with you as a patient. A scientist is more distant from you than your doctor and also there's no contract between you and the scientist.

Hey Eric
when do you think our physician will be obligated to try to help us with xmrv? I told mine and his response so far was to send me a cbt exercise study on Fm being successful.
seems like its going to be years until they are "obligated"?

She also leaves out the fact that the CDC has tested positive samples from both the WPI and from the FDA and found them all negative. If those samples were positive due to contamination, why did the CDC's assays not pick up the alleged contaminants?

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is it possible that something in, say, the lab equipment, at the FDA and WPI could cause contamination, and that could explain why the CDC did not find anything in the positive samples? that is, the samples themselves have no XMRV/MLV in them?

is it possible that something in, say, the lab equipment, at the FDA and WPI could cause contamination, and that could explain why the CDC did not find anything in the positive samples? that is, the samples themselves have no XMRV/MLV in them?

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One of the interesting questions for that particular theory to answer would be: How then did the Swedish study find 3/5 positives in the samples Dr Mikovits sent them, and not in any of the other samples their study tested? The only contamination theory that could explain those findings is contamination of the samples, not the equipment.

If you take all the evidence together, it's just incredibly hard to see how contamination could explain all the different results. Engineering such an explanation is beyond me, for sure; I can't get my head round what the contamination theory actually is.

The whole allegation is also a pretty direct attack on researchers like Dr Mikovits, Dr Alter and Dr Lo to contradict them when they emphasise the steps they have taken to rule out contamination.

The WPI have also asserted, at a very early stage (ie nearly a year ago), that the samples were sent to the independent labs coded and blinded, and as Dr Yes has emphasised so well, this was also dealt with in the follow-up Q&A to the Lombardi study. So the WPI are clearly asserting that they have achieved strong results in blinded tests, and it seems to me that any query about this is basically saying "we don't believe you".

I have always felt that, regardless of what the Science study says about blinding, the Lombardi team would have to all be very confident about the XMRV-CFS connection in order to put their professional reputations on the line so clearly as they have. Since all these researchers are clearly not stupid, and have been researching XMRV and CFS for some years now, to me it beggars belief that they could have deceived themselves about their methodology. The published studies are surely the tip of the iceberg; the WPI have surely been testing other patients and other controls, they have masses more results than we have seen in published information, and since they're still confident in their results, this is ultimately the factor that has been the source of my confidence in the accuracy of their findings. Dr McClure, on the other hand, only has to be confident that she can't find anything, just as Dr Huber only has to be confident that her lab was contaminated - all of which counts for much, much less.

PS one further point about 'contamination' which seems crucial to me: the exact same controversy exists with the prostate cancer studies, between 0/0 studies and studies that do find XMRV. Dr McClure is reported here as seeming to believe the prostate cancer association but not the CFS association.

I find that position quite bizarre. All the positive studies in PC have found background levels of XMRV in the healthy controls as well, around 2-8%, and even in one case (Germany) in the same country as a 0/0 study. In order for the 0/0 studies to be valid, one would have to say that all the prostate cancer studies, too, have a contamination or methodology problem that is picking up far too many false positives in the general population.

So one would also have to say that all the prostate cancer studies are flawed as well! And in Dr Singh's case, she has found a correlation between severity of PC prognosis and level of XMRV infection. That's a very strong finding indeed IMO.

I just don't see how you can take both the prostate cancer results and the CFS results, examine those studies in detail, and then still say that the 0/0 studies that found no XMRV in the background population, are correct. Every new study that comes in - whether positive or negative - just adds to the weight of evidence that says that "failure to detect" means no more and no less than "failure to detect".

i agree with all your points. i am just trying to see if there is any even remote chance of a screw up here, and it's hard to find.

on the other hand, i have to say, as a lay person, it is also confusing how supposedly reputable research scientists don't know which test tubes to use (e.g. not heparin). and i don't think poor patient selection can explain it all, as u have to figure even the cdc picked some pwc's and should have found at least 1 positive.

either way, i think our answers will come within a few months, and i think the wpi/nih/cc/fda will be vindicated.

is it possible that something in, say, the lab equipment, at the FDA and WPI could cause contamination, and that could explain why the CDC did not find anything in the positive samples? that is, the samples themselves have no XMRV/MLV in them?

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Hi Jim

Among other things, that wouldn't explain how the NCI detected XMRV in the samples as well; that must mean the alleged 'contamination' was in the samples, as the two labs do not share equipment!

Hey Eric
when do you think our physician will be obligated to try to help us with xmrv? I told mine and his response so far was to send me a cbt exercise study on Fm being successful.
seems like its going to be years until they are "obligated"?

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Hey xrayspex

I just saw your question. I'm away from home now, spent the night in the train (not much sleep, but at least you have a bed), so right now i can't answer. I'll try to answer later, when i'm hopefully in some better shape.

Depends what you mean by "obligated." Insurance? I think we are looking at a pretty long wait before insurance routinely covers new treatments for XMRV.

At the moment there is no standard of care regarding XMRV, no general acceptance that it causes disease or is even found in patients, and no FDA-approved treatments for CFS per se. Doctors, however, are free to use their professional judgement to prescribe medications off-label. Whether YOUR doctor will do this is another question.

xrayspex, do you have a diagnosis of fibromyalgia? If not, i would ask your doctor whether he/she believes you have fibromyalgia based on sending this article. If you do, I would ask your doctor whether he/she is making a recommendation for your treatment. Do you expect your doctor to take some action regarding XMRV right now? I think we're still at the stage where 99.99 percent of doctors consider it premature to treat patients for XMRV. One could always go looking for one of the rare exceptions, but converting your own doctor is probably not possible at this point if he/she is not already very receptive.